Technical Field
The present invention relates to the field of biomaterials, life science and medicines, and in particular, to a monodisperse polyethylene glycol preparation and separation process, to obtain a monodisperse polyethylene glycol.
Related Art
Polyethylene glycol has an excellent biocompatibility, and functionalized polyethylene glycol can modify a bioactive molecule. After being grafted to a bioactive molecule such as a drug molecule, water solubility, biocompatibility and stability of functionalized polyethylene glycol may be improved, and toxicity thereof is reduced. The polyethylene glycol is an important intermediate for achieving delivery and controlled release of a drug. However, industrial grade polyethylene glycol is generally prepared by stepwise addition polymerization of ethylene oxide and water or ethylene glycol. The product is a mixture of polyethylene glycols with different but similar molecular weights, similar molecular structures, and wide molecular weight distribution, and cannot be separated by using a conventional separation method nor directly used for drug modification. An indicator for evaluating the range of molecular weight distribution thereof is represented by a polydispersity index. The polydispersity index is an important concept in the polymer science, and sometimes called molecular weight distribution coefficient, dispersity and the like. The polydispersity index is defined as a ratio of weight-average molecular weight to number-average molecular weight, and represented by Mw/Mn.
At present, polyethylene glycol used as a carrier of a drug or bioactive molecule is separated by using a preparative high performance liquid chromatography column. The column efficiency is over 10,000 theoretical plates, and the required polydispersity index is less than 1.1. Currently, polyethylene glycol has a minimum polydispersity index of 1.04. However, preparation conditions according to the method are rigorous, and requirements for purity of reagents and solvents are extremely high. As a result, large-scale production is not easily achieved. In addition, the product is still a mixture of polyethylene glycols with different molecular weights, and thus, it is difficult to ensure reproducibility of drug efficiency and performance of a bioactive molecule. Therefore, high purity monodisperse polyethylene glycol is a focus of research and application of a bioactive molecule such as a drug molecule. According to Chen et al., monodisperse polyethylene glycol was prepared by synthesis of triphenylmethyl polyethylene glycol and polyethylene glycol p-toluenesulfonate. In the method, the synthetic route requires a long duration, and the starting material has very similar properties with the by-products and is difficultly removed from the products. Davis et al. reacted a small-molecule polyethylene glycol with a bifunctionalized polyethylene glycol or a functionalized polyethylene glycol intermediate having a single protecting group, to achieve growth of a polyethylene glycol chain. The method has main disadvantages as follows: an expensive palladium-carbon catalyst needs to be used for hydrogenation and deprotection under high pressure, and in addition, due to a functionalized polyethylene glycol being used as a starting material, there is a very great limit to the source of the starting material, which inevitably leads to an improved cost. As a result, the price is generally very high.